It is important that the dosage of any drug fall within a therapeutic window. The therapeutic window is defined at its lower boundary by the minimum concentration required to exert a therapeutic effect, and at its upper boundary by the concentration at which unacceptable toxicity effects are observed. A difficulty with some therapeutic agents, including chemotherapeutic agents such as 5-fluorouracil, is that they possess high toxicity and/or a fast clearance rate. This results in difficulties dosing within the therapeutic window. The dosing method generally employed for drugs that possess these properties often results in administration of a supra-optimal dose that rapidly falls to a sub-optimal level between administrations.
Several divergent approaches have been employed in an attempt to improve dosage regimes of therapeutic agents.
One approach is to chemically modify the active therapeutic agent and generate a prodrug. In vivo the prodrug is converted, for example, by hydrolytic, oxidative, reductive or enzymatic cleavage to the biologically active agent.
One such drug that has been successful converted into a prodrug is the 5-fluorouracil (5-FU) prodrug, such as Capecitabine or its analogues. Compounds of this nature are disclosed in a general sense in U.S. Pat. No. 4,966,891 and equivalent application EP 0316704 (F. Hoffmann-La Roche AG). Capecitabine undergoes three chemical conversions in vivo to generate 5-fluorouracil, namely: carboxylesterase-catalysed hydrolysis to generate 5′-deoxy-5-fluorocytidine; conversion of 5′-deoxy-5-fluorocytidine to 5′-deoxy-5-fluorouridine catalysed by cytidine deaminase, followed by conversion of 5′-deoxy-5-fluorouridine to active 5-FU preferentially at tumour sites catalysed by the angiogenic factor thymidine phosphorylase. In spite of being less toxic than 5-FU, Capecitabine and its analogues still possess substantial drawbacks; namely, they still possess an undesirable rapid clearance rate.
Another approach to prolong clearance is to encapsulate or otherwise non-covalently incorporate the biologically active drug or prodrug into a drug delivery vehicle or matrix. One investigated material is a biologically inert amphiphilic matrix. Amphiphiles are compounds that possess a hydrophilic portion and a hydrophobic portion. Under certain conditions, amphiphiles spontaneously aggregate, or self-assemble, into structures that possess at least some degree of internal order. The self-assembly behaviour of amphiphiles in solvent arises because of the preferential interaction between the solvent and either the hydrophilic or hydrophobic portion of the amphiphilic molecule. When an amphiphile is exposed to a polar solvent, the hydrophilic portion of the amphiphile tends to preferentially interact with the polar solvent, resulting in the formation of hydrophilic domains (‘solvent domain’). The hydrophobic portion of the amphiphile molecules tend to be excluded from this domain, resulting in the de facto formation of a hydrophobic domain (‘amphiphile domain’). Such self-generated aggregates are referred to throughout the specification as self-assembled structures. When being used as a drug delivery vehicle, the amphiphile self-assembled structure acts as an inert carrier of the biologically active agent. Amphiphile self-assembled structures represent promising drug-delivery vehicles, because the presence of both hydrophilic and hydrophobic domains potentially allows for the incorporation of both polar and non-polar active agents into the structure.
As self-assembled structures may exhibit a variety of orientational orders, these will be discussed here for clarity. If long-range orientational order is observed within the self-assembled structure at equilibrium, the self-assembled structure is termed a ‘mesophase’, a ‘lyotropic liquid crystalline phase’, a ‘lyotropic phase’ or, as used herein, simply a ‘phase’ of ‘bulk phase’. Note that as well as the lyotropic liquid crystalline phase, there is another principal type of liquid crystalline phase, namely, the: thermotropic liquid crystalline phase. Thermotropic liquid crystals can be formed by heating a crystalline solid or by cooling an isotropic melt of an appropriate solute. Lyotropic liquid crystals may be formed by addition of a solvent to an appropriate solid or liquid amphiphile. The manipulation of parameters such as amphiphile concentration and chemical structure, solvent composition, temperature and pressure may result in the amphiphile-solvent mixture adopting lyotropic phases with distinctive characteristics.
Lyotropic phases may be classified in terms of the curvature of the interface between the hydrophilic and hydrophobic domains. The curvature between these domains is dependent upon several factors, including the concentration and molecular structure of the amphiphile. When the interface displays net curvature towards the hydrophobic domain, the phase is termed ‘normal’. When the interface displays net curvature towards the hydrophilic domain, the phase is termed ‘reverse’ or ‘inverse’ (used interchangeably herein). If the net curvature of the system approaches zero, then the resulting phase may possess a lamellar-type structure that consists of planar amphiphile bilayers separated by solvent domains. Alternatively, the net curvature may approach zero if each point on the surface is as convex in one dimension as it is concave in another dimension; such phases are referred to as ‘minimal surface’ phases. Examples of particular phases that can be formed by self-assembled structures include but are not limited to: micellar (normal and reversed), hexagonal (normal and reversed), lamellar, cubic (normal, reversed and bicontinuous), and other intermediate phases such as reverse micellar cubic, the ribbon, mesh, or non-cubic ‘sponge’ bicontinuous phases.
Also, as well as the bulk phases described above, amphiphile self-assembled structure may be dispersed to form colloidal particles (so-called ‘colloidosomes’) that retain the internal structure of the non-dispersed bulk phase. When these particles possess the internal structure of a reversed bicontinuous cubic phase, the particles are colloquially referred to as cubosomes. Similarly, when the particles possess the internal structure of a reversed hexagonal phase, they are referred to as hexosomes. When the particles possess the internal structure of a lamellar phase, they are referred to as liposomes. Colloidal particles may also be formed from ‘sponge’ phases.
Another form of amphiphile self-assembled structure that has been utilised for drug delivery applications are solid lipid particles. Solid lipid particles are comprised of a solid lipid core stabilised by a surfactant surface layer, such as polysorbate 80.
As mentioned above, certain of these amphiphile self-assembled structures comprising biologically inert amphiphiles have been investigated for drug-delivery applications. These self-assembled structures are intended to act as an inert matrix or carrier into which biologically active molecules may be non-covalently incorporated. For instance, EP 0 126 751 B2 discloses the use of bulk cubic and reversed hexagonal phases for drug delivery applications. Certain of the colloidal particles have also been investigated for their application as drug delivery vehicles. For instance, U.S. Pat. No. 5,531,925 discloses colloidal particles comprising an interior of an amphiphilic-based phase, surrounded by a surface phase anchored to the bi- or mono-layer of the interior phase. The interior phase of the particles of U.S. Pat. No. 5,531,925 may be selected from reversed cubic, hexagonal or intermediate, or L3 (‘sponge’) phases, or mixtures thereof. Certain solid lipid particles have been used as carriers for hydrophobic drugs. For example Campothecin, an anticancer agent which was mixed with an amphiphile, stabilised by poloxamer and then dispersed by homogenisation into solid lipid particles demonstrated increased drug levels in the brain tissues (Yang 1999).
Unfortunately, the self-assembled structures/drug delivery vehicles described above possess properties that make them unsuitable for their intended application, the undesirable properties including (i) toxicity, (ii) inappropriate absorption, distribution, metabolism and excretion profiles, and (iii) inappropriate biodegradability properties. Moreover, it is often difficult to achieve sufficient drug loadings into the structure such that a therapeutic effect is observed when the drug delivery vehicle is administered.
In an effort to increase drug loadings, the “pharmacosome” approach has been employed. This approach involves generating a prodrug that is capable of assembling into a micelle or liposome. Jin et al. identify some lipid-nucleoside analogues that can form normal lamellar vesicles (Jin 2005, Zhang 2006). However, micelles and liposomes also possess substantial drawbacks as phases suitable for drug delivery. For instance, micellar systems can disintegrate under dilution and below the critical micelle concentration (CMC). Additionally, oral application of liposomes is limited due to the fast uptake of the liposomes by phagocytes of the immune systems in stomach and duodenum.
All of the above-described approaches suffer from substantial drawbacks. Accordingly, there remains a need to generate better methods of drug delivery.
Reference to any prior art in the specification is not, and should not be taken as, an acknowledgment or any form of suggestion that this prior art forms part of the common general knowledge in Australia or any other jurisdiction or that this prior art could reasonably be expected to be ascertained, understood and regarded as relevant by a person skilled in the art.